Treatment of Women with Epilepsy

ABSTRACT

Epilepsy is equally prevalent in men and women. However, for women there are unique concerns related to hormone effects on seizures and the effects of seizures and antiepileptic drugs (AEDs) on reproductive health. Steroid hormones affect neuronal excitability and seizure frequency. Some AEDs reduce the efficacy of oral contraceptive agents, increasing the probability of unplanned pregnancies. AEDs affect bone density. AEDs may alter reproductive hormones resulting in polycystic-appearing ovaries, anovulatory cycles, and infertility. Seizure frequency may change during pregnancy, seizures may cause pregnancy complications, some AEDs are teratogenic, and many cross into breast milk. The treatment of a woman with epilepsy must consider all these issues.

KEYWORD

Steroid hormones - catamenial seizures - oral contraception - bone health - reproductive health - pregnancy

REFERENCES

• 1 Pfaff D W, McEwen B S. Actions of estrogens and progestins on nerve cells.  Science . 1983;  219 808-814
• 2 McEwen B S. Multiple ovarian hormone effects on brain structure and function.  J Gend Specif Med . 1998;  1 33-41
• 3 Woolley C S, Schwartzkroin P A. Hormonal effects on the brain.  Epilepsia . 1998;  39 (suppl 8) S2-S8
• 4 Thomas J, McLean J H. Castration alters susceptibility of male rats to specific seizures.  Physiol Behav . 1991;  49 1177-1179
• 5 Finn D A, Gee K W. The estrous cycle, sensitivity to convulsants and the anticonvulsant effect of a neuroactive steroid.  J Pharmacol Exp Ther . 1994;  271 164-170
• 6 Wooley D E, Timiras P S. Estrous and circadian periodicity and electroshock convulsions in rats.  Am J Physiol . 1962;  202 379-382
• 7 Wooley D E, Timiras P S. The gonad-brain relationship: effects of female sex hormones and electroshock convulsions in the rat.  Endocrinology . 1962;  70 196-209
• 8 Marcus E M, Watson C W, Goldman P L. Effects of steroids on cerebral electrical activity: epileptogenic effects of conjugated estrogens and related compounds in the cat and rabbit.  Arch Neurol . 1966;  15 521-532
• 9 Stitt S L, Kinnard W J. The effect of certain progestins and estrogens on the threshold of electrically induced seizure patterns.  Neurology . 1968;  18 213-216
• 10 Hom A C, Buterbaugh G G. Estrogen alters the acquisition of seizures kindled by repeated amygdala stimulation or pentylenetetrazol administration in ovariectomized female rats.  Epilepsia . 1986;  27 103-108
• 11 Spiegel E, Wycis H. Anticonvulsant effects of steroids.  J Lab Clin Med . 1945;  30 947-953
• 12 Landgren S, Backstrom T, Kalistratov G. The effect of progesterone on the spontaneous interictal spike evoked by the application of penicillin to the cat's cerebral cortex.  J Neurol Sci . 1976;  36 119-133
• 13 Holmes G L, Kloczko N, Weber D A, Zimmerman A W. Anticonvulsant effect of hormones on seizures in animals. In: Porter RJ, Mattson RH, Ward AM Jr, Dam M, eds. Advances in Epileptology: XVth Epilepsy International Symposium New York: Raven Press 1984: 265-268
• 14 Tauboll E, Lindstrom S. The effect of progesterone and its metabolite 5-alpha-pregnan-3-alpha-ol-20-one on focal epileptic seizures in the cat's visual cortex in vivo.  Epilepsy Res . 1993;  14 17-30
• 15 Finn D A, Roberts A J, Crabbe J C. Neuroactive steroid sensitivity in withdrawal seizure-prone and resistant mice.  Alcoholism Clin Exp Res . 1995;  19 410-415
• 16 Brann D W, Hendry L B, Mahesh V B. Emerging diversities in the mechanism of action of steroid hormones.  J Steroid Biochem Mol Biol . 1995;  52 113-133
• 17 Herzog A G, Klein P, Ransil B J. Three patterns of catamenial epilepsy.  Epilepsia . 1997;  38 1082-1088
• 18 Mattson R H, Cramer J A, Caldwell B V, Siconolfe B C. Treatment of seizures with medroxyprogesterone acetate: preliminary report.  Neurology . 1984;  34 1255-1258
• 19 Herzog A G. Reproductive endocrine considerations and hormonal therapy for women with epilepsy.  Epilepsia . 1991;  32 (suppl 6) 527-533
• 20 Herzog A G. Progesterone therapy in women with complex partial and secondary generalized seizures.  Neurology . 1995;  45 1660-1662
• 21 Abbasi F, Krumholz A, Kittner S J, Langenberg P. Effects of menopause on seizures in women with epilepsy.  Epilepsia . 1999;  40 205-210
• 22 Harden C L, Pulver M C, Ravdin L, Jacobs A R. The effect of menopause and perimenopause on the course of epilepsy.  Epilepsia . 1999;  40 1402-1407
• 23 Coulam C B, Annegers J F. Do oral anticonvulsants reduce the efficacy of oral contraceptives?.  Epilepsia . 1979;  20 519-526
• 24 Mattson R H, Cramer J A, Darney P D, Naftolin F. Use of oral contraceptives by women with epilepsy.  JAMA . 1986;  256 238-240
• 25 Perrucca E. Clinical implications of hepatic microsomal enzyme induction by antiepileptic drugs.  Pharmacol Ther . 1987;  33 139-144
• 26 McAuley J W, Anderson G D. Treatment of epilepsy in women of reproductive age: pharmacokinetic considerations.  Clin Pharmacokinet . 2002;  41 559-579
• 27 Zahn C A, Morrell M J, Collins S D, Collins S D, Labiner D M, Yerby M S. Management issues for women with epilepsy: a review of the literature. American Academy of Neurology Practice Guidelines.  Neurology . 1998;  51 949-956
• 28 American Academy of Neurology. Quality Standards Subcommittee. Practice parameter: management issues for women with epilepsy (summary statement).  Neurology . 1998;  51 944-948
• 29 Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment.  Contraception . 1986;  33 559-565
• 30 Odlind V, Olsson S E. Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with Norplant implants.  Contraception . 1986;  33 257-261
• 31 Krauss G L, Brandt J, Campbell M, Plate C, Summerfield M. Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians.  Neurology . 1996;  46 1534-1539
• 32 Morrell M J, Sarto G E, Osborne Shafer P, Borda E A, Herzog A, Callanan M. Health issues for women with epilepsy: a descriptive survey to assess knowledge and awareness among healthcare providers.  J Womens Health Gend Based Med . 2000;  9 959-965
• 33 Chang S, Ahn C. Effects of antiepileptic drug therapy on bone mineral density in ambulatory epileptic children.  Brain Dev . 1994;  16 382-385
• 34 Valimaki M, Tiihonen M, Laitinen K. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs.  J Bone Miner Res . 1994;  9 631-637
• 35 Sheth R, Wesolowski C, Jacob J. Effect of carbamazepine and valproate on bone mineral density.  J Pediatr . 1996;  127 256-262
• 36 Cummings S R, Nevitt M C, Browner W S. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.  N Engl J Med . 1995;  332 767-773
• 37 Bogliun G, Beghi E, Crespi V, Delodovick L, d'Amico P. Anticonvulsant drugs and bone metabolism.  Acta Neurol Scand . 1986;  74 284-288
• 38 Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in outpatients with epilepsy.  Q J Med . 1986;  59 569-577
• 39 Takeshita N, Seino Y, Ishida H. Increased circulating levels of gamma-carboxyglutamic acid-containing protein and decreased bone mass in children on anticonvulsant therapy.  Calcif Tissue Int . 1989;  44 80-85
• 40 Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic patients treated with carbamazepine.  Ann Neurol . 2000;  47 385-388
• 41 Sato Y, Kondo I, Ishida S. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy.  Neurology . 2001;  57 445-449
• 42 Koch H V, Kraft D, von Herrath D. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat.  Epilepsia . 1972;  13 829-834
• 43 Kruse K, Suss A, Busse M, Schneider P. Monomeric serum calcitonin and bone turnover during anticonvulsant treatment and in congenital hypothyroidism.  J Pediatr . 1987;  111 57-63
• 44 Weinstein R S, Bryce G F, Sappington L J. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment.  J Clin Endocrinol Metab . 1984;  58 1003-1009
• 45 Vernillo A T, Rifkin B R, Hauschka P V. Phenytoin affects osteoblastic secretion from osteoblastic rat osteosarcoma 17/2.8 cells in culture.  Bone . 1990;  11 309-312
• 46 Dansky L V, Andermann E, Andermann F. Marriage and fertility in epileptic patients.  Epilepsia . 1980;  21 261-271
• 47 Webber M P, Hauser W A, Ottman R, Annegers J F. Fertility in persons with epilepsy:1935-1974.  Epilepsia . 1986;  27 746-752
• 48 Schupf N, Ottman R. Likelihood of pregnancy in individuals with idiopathic/cryptogenic epilepsy: social and biologic influence.  Epilepsia . 1994;  35 750-756
• 49 Schupf N, Ottman R. Reproduction among individuals with idiopathic/cryptogenic epilepsy: risk factors for reduced fertility in marriage.  Epilepsia . 1996;  37 833-840
• 50 Wallace H, Shorvon S, Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy.  Lancet . 1998;  352 1970-1973
• 51 Herzog A G, Seibel M M, Schomer D L, Vaitukaitis J L, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin.  Arch Neurol . 1986;  43 341-346
• 52 Meo R, Bilo L, Nappi C. Derangement of the hypothalamic GnRH pulse generator in women with epilepsy.  Seizure . 1993;  2 241-252
• 53 Dana-Haeri J, Trimble M R, Oxley J. Prolactin and gonadotrophin changes following generalized and partial seizures.  J Neurol Neurosurg Psychiatry . 1983;  46 331-335
• 54 Sperling M R, Pritchard P B, Engel J, Daniel C, Sagel J. Prolactin in partial epilepsy: an indicator of limbic seizures.  Ann Neurol . 1986;  20 716-722
• 55 Bilo L, Meo R, Valentino R, Buscaino G A, Straino S, Nappi C. Abnormal pattern of luteinizing hormone pulsatility in women with epilepsy.  Fertil Steril . 1991;  55 705-711
• 56 Drislane F W, Coleman A E, Schomer D L. Altered pulsatile secretion of luteinizing hormone in women with epilepsy.  Neurology . 1994;  44 306-310
• 57 Morrell M J, Guidice L, Flynn K L. Predictors of ovulatory failure in women with epilepsy.  Ann Neurol . 2002;  52 704-711
• 58 Isojarvi J IT, Rattya J, Myllyla V V. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy.  Ann Neurol . 1998;  43 446-451
• 59 Morrell M J, Flynn K L, Seale C G. Reproductive dysfunction in women with epilepsy: antiepileptic drug effects on sex-steroid hormones.  CNS Spectrums . 2001;  6 771-786
• 60 Morrell M J. Sexuality in epilepsy. In: Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook New York: Lippincott-Raven 1997: 2021-2026
• 61 Knochenhauer E S, Key T J, Kahsar-Miller M, Waggoner W, Boots L R, Azziz R. Prevalence of the polycystic syndrome in unselected black and white women of the southeastern United States: a prospective study.  J Clin Endocrinol Metab . 1998;  83 3078-3082
• 62 Ben-Shlomo I, Franks S, Adashi E Y. The polycystic ovary syndrome: nature or nurture?.  Fertil Steril . 1995;  63 953-954
• 63 Lobo R A. A disorder without identity: "HCA," "PCO," "PCOD," "PCOS," "SLS." What are we to call it?!.  Fertil Steril . 1995;  63 1158-1160
• 64 Clayton R N, Ogden V, Hodgkinson J. How common are polycystic ovaries in normal women and what is their significance for the fertility of the population?.  Clin Endocrinol (Oxf) . 1992;  37 127-134
• 65 Isojarvi J IT, Laatikainen T J, Pakarinen A J, Juntunen K TS, Myllyla V V. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy.  N Engl J Med . 1993;  329 1383-1388
• 66 Biton V, Mirza W, Montouris G, Vuong A, Hammer A E, Barrett P S. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.  Neurology . 2001;  56 172-177
• 67 Morrell M J, Guldner G T. Self-reported sexual function and sexual arousability in women with epilepsy.  Epilepsia . 1996;  37 1204-1210
• 68 Dana-Haeri J, Oxley J. Reduction of free testosterone by antiepileptic drugs.  Br Med J . 1982;  284 85-86
• 69 Luhdorf K. Endocrine function and antiepileptic treatment.  Acta Neurol Scand . 1983;  67 (suppl 94) 15-19
• 70 Mattson R H, Cramer J A, Collins J F. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.  N Engl J Med . 1985;  313 145-151
• 71 Beastall G H, Cowan R A, Gray J MB, Fogelman I. Hormone binding globulins and anticonvulsant therapy.  Scott Med J . 1985;  30 101-105
• 72 Fenwick P BC, Mercer C, Grant R. Nocturnal penile tumescence and serum testosterone levels.  Arch Sex Behav . 1986;  15 13-21
• 73 Fisher R S, Vickrey B G, Gibson P. The impact of epilepsy from the patient's perspective I. Descriptions and subjective perceptions.  Epilepsy Res . 2000;  41 39-51
• 74 Schmidt D, Beck-Mannagetta G, Janz D, Koch S. The effect of pregnancy on the course of epilepsy: a prospective study. In: Janz D, Dam M, Richens A, eds. Epilepsy, Pregnancy and the Child New York: Raven Press 1982: 39-49
• 75 Hauser W A, Hesdorffer D C. Risk factors. In: Hauser WA, Hesdorffer DC, eds. Epilepsy: Frequency, Causes and Consequences New York: Demos 1990: 53-100
• 76 Yerby M, Morrell M J. Efficacy, safety and tolerability of zonisamide in women. Sexual dysfunction and hormonal abnormalities in women with epilepsy.  Epilepsia . 2000;  41 (suppl 7) 199
• 77 Schupf N, Ottman R. Reproduction among individuals with idiopathic/cryptogenic epilepsy: risk factors for spontaneous abortion.  Epilepsia . 1997;  38 824-829
• 78 Steegers-Theunissen R PM, Renier W O, Borm G F. Factors influencing the risk of abnormal pregnancy outcome in epileptic women: a multicentre prospective study.  Epilepsy Res . 1994;  18 261-269
• 79 Teramo K, Hiilesmaa V, Brady A, Saarikoski S. Fetal heart rate during a maternal grand mal epileptic seizure.  J Perinatal Med . 1979;  7 3-6
• 80 Gaily E, Granstrom M L. Minor anomalies in children of mothers with epilepsy.  Neurology . 1992;  42 (suppl 5) 128-131
• 81 Annegers J F, Hauser W A, Elveback L R, Anderson V E, Kurland L T. Congenital malformations and seizure disorders in the offspring of parents with epilepsy.  Int J Epidemiol . 1978;  7 241-247
• 82 Friis M L. Facial clefts and congenital heart defects in children of parents with epilepsy: genetic and environmental etiologic factors.  Acta Neurol Scand . 1989;  79 433-459
• 83 Koch S, Loesche G, Jager-Roman E. Major birth malformations and antiepileptic drugs.  Neurology . 1992;  42 (suppl 5) 83-88
• 84 Rosa F W. Spina bifida in infants of women treated with carbamazepine during pregnancy.  N Engl J Med . 1991;  324 674-677
• 85 Omtzigt J GC, Los F J, Grobee D E. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort.  Neurology . 1992;  42 (suppl 5) 119-125
• 86 Holmes L B, Harvey E A, Coull B A. The teratogenicity of anticonvulsant drugs.  N Engl J Med . 2001;  344 1132-1138
• 87 Gaily E, Kantola-Sorsa E, Granstrom M L. Intelligence of children of epileptic mothers.  J Pediatr . 1988;  113 677-684
• 88 Koch S, Titze K, Zimmerman R B, Scroder M, Lehmkuhl U, Rauh H. Long-term neuropsychological consequences of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents.  Epilepsia . 1999;  40 1237-1243
• 89 Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy.  J Neurol Neurosurg Psychiatry . 2001;  70 15-21
• 90 Finnell R H, Buehler B A, Kerr B M, Ager P L, Levy R H. Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis.  Neurology . 1992;  42 25-31
• 91 Miranda A F, Wiley M J, Wells P G. Evidence for embryonic peroxidase-catalyzed bioactivation and glutathione-dependent cytoprotection in phenytoin teratogenicity: modulation by eicosatetraynoic acid and buthione sulfoximine in murine embryo culture.  Toxicol Appl Pharmacol . 1994;  124 230-241
• 92 Buehler B A, Delimont D, Van Waes M, Finnell R H. Prenatal prediction of risk of the fetal hydantoin syndrome.  N Engl J Med . 1990;  322 1567-1572
• 93 Finnell R H. Genetic differences in susceptibility to anticonvulsant drug induced developmental defects.  Pharmacol Toxicol . 1991;  69 223-227
• 94 Strickler S M, Dansky L V, Miller M A, Seni M H, Andermann E, Spielberg S P. Genetic predisposition to phenytoin-induced birth defects.  Lancet . 1985;  2 746-749
• 95 Nau H, Tzimas G, Mondry M, Plum C, Spohr H L. Antiepileptic drugs alter endogenous retinoid concentration: a possible mechanism of teratogenesis of anticonvulsant therapy.  Life Sci . 1995;  57 53-60
• 96 Tomson T, Lindbom U, Sundqvist A, Berg A. Red cell folate levels in pregnant epileptic women.  Eur J Clin Pharmacol . 1995;  48 305-308
• 97 Laurence K M, James N, Miller M H, Tennant G B, Campbell H. Double-blind, randomized controlled trial of folate treatment before conception to prevent the recurrence of neural tube defects.  Br Med J . 1981;  282 1509-1511
• 98 Dansky L, Andermann E, Roseblatt D, Sherwin A L, Andermann F. Anticonvulsants, folate levels and pregnancy outcome.  Ann Neurol . 1987;  21 176-182
• 99 Yates J RW, Ferguson-Smith M A, Shenkin A, Guzman-Rodriguez R, White M, Clark B J. Is disordered folate metabolism the basis for the genetic predisposition to neural tube defects?.  Clin Genet . 1987;  31 279-287
• 100 Mulinare J, Corder J F, Erickson J D. Periconceptional use of multivitamins and the occurrence of neural tube defects.  JAMA . 1988;  260 3141-3145
• 101 Werler M M, Shapiro S, Mitchell A A. Periconceptional folic acid exposure and risk of occurrent neural tube defects.  JAMA . 1993;  269 1257-1261
• 102 Milunsky A, Jick H, Jick S S. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects.  JAMA . 1988;  262 2847-2852
• 103 Daly L E, Kirke P N, Molloy A, Weir D G, Scott J M. Folate levels and neural tube defects: implications for treatment.  JAMA . 1995;  274 1698-1702
• 104 Gordon N. Folate metabolism and neural tube defects.  Brain Dev . 1995;  17 307-311
• 105 Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep .  1992;  41 1-7
• 106 Ogawa Y, Kaneko S, Otani K, Fukushima Y. Serum folic acid levels in epileptic mothers and their relationship to congenital malformations.  Epilepsy Res . 1991;  8 75-78
• 107 Oguni M, Dansky L, Andermann E, Sherwin A, Andermann F. Improved pregnancy outcome in epileptic women in the last decade: relationship to maternal anticonvulsant therapy.  Brain Dev . 1992;  14 371-380
• 108 Hernandez-Diaz S, Werler M M, Walker A M. Folic acid antagonists during pregnancy and the risk of birth defects.  N Engl J Med . 2000;  343 1608-1614
• 109 Craig J, Morrison P, Morrow J. Failure of periconceptional folic acid to prevent a neural tube defect in the offspring of a mother taking sodium valproate.  Seizure . 1999;  8 253-254
• 110 Seizure disorders in pregnancy. American College of Obstetric and Gynecologic Physicians Educational Bulletin .  1996;  231 1-13
• 111 Van Allen M, Fraser F C, Dallaire L. Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects.  Can Med Assoc J . 1993;  149 1239-1243
• 112 Commission on Genetics, Pregnancy, and the Child, International League Against Epilepsy. Guidelines for the care of women of childbearing age with epilepsy.  Epilepsia . 1993;  34 588-589
• 113 Thorp J A, Gaston L, Caspers D R, Pal M L. Current concepts and controversies in the use of vitamin K.  Drugs . 1995;  49 376-387
• 114 American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk.  Pediatrics . 1994;  93 137-150